When was dacarbazine approved for melanoma

A Phase I study in patients with advanced cancer including 54 patients with melanoma demonstrated that BMS, a fully human anti-CD agonist monoclonal antibody, had clinical activity justifying its further evaluation both as a single agent and in combination therapy [ 87 ]. A study combining anti-CD and ipilimumab in patients with melanoma was designed but was subsequently withdrawn prior to enrolment ClinicalTrials. Sorafenib has been shown to inhibit MAPK pathway in vitro and in vivo [ 92 ].

As a single-agent, sorafenib is well tolerated but it has not shown significant anti-tumour activity in advanced melanoma patients [ 94 ]. Neither has the addition of sorafenib to carboplatin and paclitaxel improved response rates and PFS [ 95 ]. However, sorafenib in combination with dacarbazine resulted in a significant improvement in PFS in patients with advanced melanoma [ 96 ]. Additionally, Su et al. However, more studies are needed to confirm the efficacy and safety of RAF and a study is already ongoing, although not recruiting participants ClinicalTrials.

Vemurafenib is an oral, reversible and selective inhibitor of BRAF VE [ ] that is approved by the FDA for the treatment of patients with nonresectable or metastatic melanoma. Vemurafenib was first evaluated by Flaherty et al.

The most common adverse events of vemurafenib were arthralgia, rash, photosensitivity, diarrhoea, mild-to-moderate nausea, fatigue and alopecia [ , ]. Vemurafenib also has activity in brain metastases in patients with BRAF VE mutation melanoma, correlated with extra-cranial tumour response [ , ]. Dabrafenib also has activity against brain metastases as it leads to reduction in the size of brain lesions [ , ]. One of the problems of selective BRAF inhibitors is the resistance acquired to treatment.

Side-effects of dabrafenib are very similar to those observed with vemurafenib, although dabrafenib is also associated with induction of keratinocytic proliferation [ ]. These mutations render melanoma cells independent of the normal RTK-mediated pathway regulation and constitutively drive melanoma cells to oncogenic proliferation and survival [ 67 ].

Direct inhibition of MEK may therefore block cell proliferation and induce apoptosis. Kirkwood et al. However, selumetinib combined with standard chemotherapeutic agents resulted in enhanced tumour growth inhibition in human tumour xenograft models [ ]. Moreover, combination of selumetinib and Rous sarcoma oncogene SRC kinase inhibitor saracatinib suppressed melanoma cell growth and invasion [ ]. Following a Phase I dose-escalation trial of trametinib in patients with advanced melanoma, Falchook et al.

Many new MEK inhibitors are being developed. Von Euw et al. Inhibition of the MEK pathway seems to be promising in the treatment of melanoma, although more studies are needed. Angiogenesis is essential to tumour growth and VEGF plays an important role in angiogenesis, regulating the proliferation and migration of endothelial cells. Rationally, blocking angiogenesis would be expected to enhance tumour inhibition, so recently bevacizumab and other anti-angiogenic agents have been tested in melanoma.

Moreover, Grignol et al. Bevacizumab in combination with carboplatin plus paclitaxel does not appear to improve PFS in patients with untreated advanced melanoma [ ]. However, von Moos et al. New studies are needed to confirm if bevacizumab has activity when combined with new agents such as ipilimumab. Fruehauf et al. Axitinib plus a specific peptide-based vaccine has also been shown to enhance antitumour efficacy [ ].

It has been shown to inhibit tumour angiogenesis [ ] and so can be useful in melanoma treatment. Boss et al. These trials will help to evaluate the possible role of lenvatinib in the treatment of melanoma. Etaracizumab MEDI is a monoclonal antibody against alphavbeta3, an important molecule for tumour-induced angiogenesis that is upregulated in metastatic melanoma [ ].

In a randomised Phase II study of etaracizumab with or without dacarbazine in patients with Stage 4 metastatic melanoma, the median OS was However, more studies are needed to evaluate the use of etaracizumab in melanoma. Oblimersen is an anti-B-cell lymphoma BCL 2 antisense oligonucleotide. An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein formation. As expression of BCL2 has been associated with chemoresistance by malignant melanoma cells, down-regulation of BCL2 by oblimersen may offer a new approach to the treatment of melanoma [ ].

In fact, compared with dacarbazine alone, oblimersen plus dacarbazine significantly improved PFS 1. Moreover, electroporation may optimise the response of melanoma to chemotherapy, as it has shown to improve the delivery of oblimersen within tumour cells in vivo in a human melanoma xenograft [ ]. Bortezomib is a tripeptide that binds the catalytic site of the 26S proteasome with high specificity and affinity, inhibiting proteasome activity [ 67 ]. Amiri et al. Moreover, in a Phase I trial of bortezomib with temozolide in patients with advanced melanoma 3 patients with primary ocular melanoma and 16 patients with primary cutaneous melanoma , Su et al.

Bortezomib has also been tested in combination with paclitaxel and carboplatin in patients with metastatic melanoma, although this combination was of limited clinical benefit and was associated with significant toxicity [ ]. Nevertheless, new agents may enhance bortezomib activity.

Sunitinib arrests growth and sensitises melanoma cells to bortezomib, so combining sunitinib with bortezomib may provide therapeutic benefit [ ]. Further studies of bortezomib are needed to evaluate the potential of this drug. As mTOR is important for tumour growth. Everolimus is an mTOR inhibitor. Everolimus combined with bevacizumab has been shown to have moderate activity and be well tolerated in the treatment of patients with metastatic melanoma [ ].

Daily everolimus plus low-dose weekly cisplatin also has anti-tumour activity in several tumour types, including melanoma [ ].

However, in a Phase II study of the mTOR inhibitor, temsirolimus, only 1 of the 33 patients with metastatic melanoma had a partial response lasting 2 months; the median time to disease progression and OS were 10 weeks and 5 months, respectively [ ]. Moreover, in a Phase I study in patients with metastatic melanoma, temsirolimus combined with sorafenib resulted in significant toxicity at higher dose levels, did not have any clinical benefit in genetically unselected patients and did not inhibit P-extracellular signal-regulated kinase PERK [ ].

Additionally, in a Phase II study of temsirolimus in combination with sorafenib in patients with untreated metastatic melanoma, only 3 4.

Mutations in c-KIT in melanoma have been reported [ ]. Curtin et al. Because of its potentially important role in melanoma oncogenesis, c-KIT may be an effective target in the treatment of melanoma. In a Phase II trial of imatinib, 28 of the patients with melanoma screened for the presence of c-KIT mutations and amplifications were treated with imatinib.

In another Phase II study of imatinib in patients with metastatic melanoma and c-KIT mutations or amplification, the overall response rate was Imatinib seems to have clinical benefit in a subset of patients who have c-KIT mutation or amplification.

However, more studies are needed to confirm if imatinib is a viable treatment for such patients. Minor et al. Moreover, a strategy combining sunitinib and bortezomib has shown therapeutic benefits [ ]. Melanoma is the fifth and seventh leading cause of cancer deaths in males and females, respectively, in the USA [ ].

There are 4 drugs currently approved by the FDA for the treatment of melanoma: dacarbazine, IL-2, ipilimumab and vemurafenib.

Ipilimumab and vemurafenib were approved in and have raised many hopes in melanoma treatment. However, they have many limitations and their side effects have limited their use and redirected investigations towards new targets. Dacarbazine, one of the oldest available drugs approved in , remains the gold standard in chemotherapy, achieving complete responses in 2.

Combining dacarbazine or other chemotherapy agents with new pharmacological agents may represent a new way to achieve better responses in patients with metastatic melanoma. For example, high doses of IL-2 can be effective but are associated with greater toxicity.

However, new data suggest that the addition of famotidine to IL-2 may decrease its toxicity as it enhances lymphokine-activated killer cell activity, whilst maintaining its activity against melanoma [ 58 ].

The CTL response is another example of the beneficial effects brought by the addition of new drugs. Although it represents a promising option for the treatment of metastatic melanoma, it is not a feasible treatment for all patients as tumour cells often escape CTL attack. However, new studies have shown that the addition of bortezomib can enhance the susceptibility of melanoma cells toward redirected CTL attack [ 67 , 68 ].

Currently, ipilimumab is the most promising drug. Although it has effective response rates, its use is limited by the severe and fatal immune-related adverse reactions. Understanding oncogenesis, growth, proliferation, survival and migration pathways of melanoma cells has provided both new targets and insights in melanoma therapy.

In fact, current advances in the knowledge of melanoma oncogenesis may represent our best hope to tackle melanoma. Vemurafenib is one of the best examples in this field. However, resistance to vemurafenib has been described. Despite all the efforts made to develop new drugs, few of them have demonstrated clinical benefits. Several of them have activity in vitro or in animal models, but they achieve poor response and survival rates when they are tested in clinical trials.

In the next years this problem will likely be overcome with better understanding of the suitability of patients for the different therapies.

There are some limitations to comparing clinical trials and different approaches to melanoma. The heterogeneity of the populations enrolled in the studies, the different approaches to treatment and the different types and localisations of melanoma included in the trials made it impossible to compare some studies. The absence of clinical trials comparing new treatment options with some of the older and established treatment options made evaluation even more difficult.

New studies must be conducted Table 2 to confirm if any of the recently developed drugs alone or in combination can lead to promising clinical benefits. Funding: The Author received an honorarium from the Publisher. National Center for Biotechnology Information , U. Journal List Drugs Context v. Drugs Context. Published online Nov Tiago Rodrigues Velho. Author information Article notes Copyright and License information Disclaimer. Professor Egas Moniz — Lisboa, Portugal, tp.

Competing interests : The Author has declared that there are no competing interests. Received Aug 16; Accepted Aug Commercial use is not permitted. This article has been cited by other articles in PMC. Abstract Background: Melanoma is one of the most aggressive cancers, and it is estimated that 76, men and women will be diagnosed with melanoma of the skin in the USA in Results: To date, there are four drugs approved by the Food and Drug Administration for melanoma dacarbazine, interleukin-2, ipilimumab and vemurafenib.

Discussion: Advances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. Keywords: abraxane, axitinib, carboplatin, bevacizumab, bortezomib, dacarbazine, dabrafenib, etaracizumab, everolimus, imatinib, ipilimumab, lenvatinib, olimersen, malignant melanoma, new therapeutic agents, paclitaxel, review, sorafenib, sunitinib, temozolomide, temsirolimus, trametinib, tremelimumab, vemurafenib.

Introduction Malignant melanoma is a tumour that arises from melanocytes or from cells that develop from melanocytes. Method Search strategy A systematic search of the literature published between January and September was conducted on drugs used in the treatment of metastatic melanoma, including approved and recently designed drugs Figure 1. Open in a separate window. Figure 1.

Selection process for the studies included in the systematic review. Inclusion criteria for studies Abstracts of identified articles were screened and studies not meeting the following inclusion criteria were omitted: i development and evaluation of a drug or a combination of drugs in metastatic melanoma; ii the drugs were administered to individuals or groups with diagnosed metastatic melanoma; iii the study included data for a number of patients and tumours, tumour response and route of drug administration; iv studies with eligible study designs: randomised clinical trials RCT , cohort studies, case-control studies and case series; v the paper was not a case study; vi the paper was published in English.

Study selection and data collection The initial search identified 14, studies for potential review. Temozolomide Temozolomide is an alkylating agent related to dacarbazine. Immunoregulatory monoclonal antibodies Ipilimumab Ipilimumab is a fully human monoclonal antibody IgG1 that has been recently approved by the FDA for the treatment of metastatic melanoma.

Anti-PD-1 Programmed death-1 PD-1 is a negative regulator of the immune system that causes immune tolerance through apoptosis of the activated lymphocyte responsible for the evasion of melanoma cells [ 79 , 80 ].

Agonistic antibodies OX44 and anti CD BB Antigen-specific memory T cells Tms are essential in the immune surveillance of residual and metastatic tumours, and the activation of Tms can be achieved by the administration of agonistic anti-CD monoclonal antibody [ 83 — 85 ].

Antiangiogenic therapy Bevacizumab Angiogenesis is essential to tumour growth and VEGF plays an important role in angiogenesis, regulating the proliferation and migration of endothelial cells.

Etaracizumab MEDI Etaracizumab MEDI is a monoclonal antibody against alphavbeta3, an important molecule for tumour-induced angiogenesis that is upregulated in metastatic melanoma [ ]. Proteasome inhibitors Bortezomib Bortezomib is a tripeptide that binds the catalytic site of the 26S proteasome with high specificity and affinity, inhibiting proteasome activity [ 67 ].

Everolimus and temsirolimus Everolimus is an mTOR inhibitor. Discussion Melanoma is the fifth and seventh leading cause of cancer deaths in males and females, respectively, in the USA [ ]. Table 1 Current drugs and potential drugs in metastatic melanoma. Table 2 Future trials in melanoma research. Footnotes Funding: The Author received an honorarium from the Publisher.

References 1. Cancer Statistics, CA Cancer J Clin. Population-based analysis of prognostic factors and survival in familiar melanoma. J Clin Oncol. J Med Genet. Cancer Epidemiol Biomarkers Prev. Role of sun exposure in melanoma. Dermatol Surg. Management of cutaneous melanoma.

N Engl J Med. Final version of AJCC melanoma staging and classification. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.

Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. Late results after complete response to chemotherapy Central Oncology Group protocols , , and A Cancer. Coates AS, Segelov E. Long term response to chemotherapy in patients with visceral metastatic melanoma.

Ann Oncol. Melanoma from darkness to promise. Am J Clin Oncol. Jpn J Clin Oncol. Multicenter phase III randomized trial of polychemotherapy CVD regimen versus the same chemotherapy CT plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma. Melanoma Res. Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients. Biochemotherapy with carmustine, cisplatin, dacarbazine, tamoxifen and low dose interleukin-2 for patients with metastatic malignant melanoma.

Chang Gung Med J. Temozolomide and unusual indications: Review of literature. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. Temozolomide for the treatment of metastatic melanoma: a systematic review. Phase 2 trial of combination thalidomide plus temozolomide in patients with metastatic malignant melanoma: Southwest Oncology Group S Temozolomide with or without radiotherapy in melanoma with unresectable brain metastases.

J Neurooncol. Temozolomide in advanced malignant melanoma with small brain metastases: can we withhold cranial irradiation? Vindesine in patients with metastatic malignant melanoma: a southwest Oncology Group study.

Wiernik PH, Einzig Taxol in malignant melanoma. J Natl Cancer Inst Monogr. Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously treated with chemotherapy. A phase II study of taxol in patients with malignant melanoma.

Invest New Drugs. A Phase II trial of vinorelbine tartrate in patients with disseminated malignant melanoma and one prior systemic therapy: a Southwest Oncology Group study. Paclitaxel and tamoxifen: An active regimen for patients with metastatic melanoma. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Phase II trial of carboplatin in advanced malignant melanoma.

Cancer Treat Rep. Mohammed MQ, Retsas S. Oxaliplatin is active in vitro against human melanoma cell lines: comparison with cisplatin and carboplatin.

Anticancer Drugs. Palliative therapy of melanoma patients with fotemustine. Inverse relationship between tumour load and treatment effectiveness.

Multicenter phase II trial of the single agent fotemustine in patients with advanced malignant melanoma. Final report of the French multicenter phase II study of the nitrosourea fotemustine in evaluable patients with disseminatd malignant melanoma including patients with cerebral metastases.

Fotemustine in the treatment of brain primary tumors and metastases. Cancer Invest. Fotemustine for the treatment of melanoma. Expert Opin Pharmacother. Lens MB, Dawes M. Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials. Randomized dose-escalation study evaluating peginterferon alfa-2a in patients with metastatic malignant melanoma.

J Immunother. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of patients treated between and High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. Results of interleukinbased treatment in advanced melanoma: a case record-based analysis of patients. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines.

Clin Cancer Res. Br J Cancer. Med Klin Munich ; 91 Suppl 3 —9. Biochemotherapy in the treatment of metastatic melanoma in selected patients. Clin Transl Oncol. Chemoimmunotherapy of advanced malignant melanoma sequential administration of subcutaneous interleukin-2 and interferon-alpha after intravenous dacarbazine and carboplatin or intravenous dacarbazine, cisplatin, carmustine and tamoxifen. Eur J Cancer. Cancer Biother Radiopharm. Bleackley RC. A molecular view of cytotoxic T lymphocyte induced killing.

Biochem Cell Biol. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc Natl Acad Sci U. Cancer regression in patients after transfer of genetically engineered lymphocytes. Adoptive immunotherapy for cancer: harnessing the T cell response.

Nat Rev Immunol. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.

Advances in the treatment of metastatic melanoma: adoptive T-cell therapy. Semin Onco. New therapeutic agents in uveal melanoma. Anticancer Res. Cancer Res. Tarhini AA, Iqbal F. CTLA-4 blockade: therapeutic potential in cancer treatments. Onco Targets Ther. Robert C, Ghiringhelli F. What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma?

Complete response was defined as disappearance of all symptoms and signs of all measurable disease, lasting for at least 4 weeks, without appearance of new lesions. Overall response included complete response and partial response. Overall survival OS was defined as the time from the date of randomization to the date of death from any cause, or the date of last follow-up for living patients. So the 1-year survival was the proportion of participants alive at 1-year follow-up.

As for the safety outcomes, we referred to the trial authors' definitions. In this meta-analysis, four frequent nonhematologic adverse events nausea, vomiting, fatigue and constipation and two frequent hematologic adverse events anemia and neutropenia were examined. Meta-analysis was performed using Review Manager Version 5. The between-studies heterogeneity was evaluated using the Chi-square test, P values, and I 2 statistics [16].

If there was statistical heterogeneity among the studies without clinical heterogeneity or the difference was no clinical significance, a random-effects model was applied. If the heterogeneity between groups was too great, or sufficiently detailed data from the original trials were not available, a descriptive analysis could be adopted. Publication bias was estimated by funnel plots using Revman 5 software [17].

We also further examined the potential of publication bias using the Begg and Egger tests. In addition, sensitivity analysis was performed to examine the influence of individual studies. The initial search resulted in 1, potential citations, of which duplicate papers were excluded. Of the remaining 1, articles, were excluded after the title and abstract were read. Then, 92 full-text articles were assessed for eligibility.

Eight possible candidates were retrieved for detailed examination by reading the full text [18] — [25]. The screening process is summarized in a flow diagram Fig. The eight included studies, with a total of 2, participants, were all RCTs conducted between and that were available as fully published papers. The characteristics of the trials included are shown in Table 1. The eight included studies were two-group parallel-design studies, so eight comparisons were included this meta-analysis.

Of all the included RCTs, none mentioned a specific randomization method, seven were blinded and five reported allocation concealment. Quality evaluations of the included studies are shown in Fig. Of those, six comparisons were used to analyze the overall response and eight comparisons to analyze the 1-year survival. The corresponding funnel plot shows a symmetric distribution of studies, indicating no publication bias Fig. The corresponding funnel plot showed no publication bias Fig.

Furthermore, the sensitivity analysis was conducted for all the outcome measures of effectiveness. The results revealed that no individual study appeared to change the pooled RR dramatically see S3 appendix for more detailed information. Nausea was reported in five trials. Vomiting was reported in four trials. Fatigue was reported in five trials. Constipation was reported in four trials. Anemia was reported in four trials.

Neutropenia was reported in five trials. Furthermore, sensitivity analysis was conducted for all safety outcome measures. The results revealed that the study conducted by Bedikian and his co-worker changed the pooled RR dramatically see We found that except for vomiting there were no significant differences in these safety outcomes between the arm for DTIC combined targeted therapy and the arm for DTIC alone. In another subgroup, there was only one study, conducted by Bedikian and his co-worker, in which we found significant differences between the arm for DTIC combined targeted therapy and the arm for DTIC alone for adverse events other than fatigue and constipation.

Malignant melanoma is a malignant tumor of neural crest origin [24]. It is formed from malignant melanocytes located at the bottom of the epidermis and is almost always evolved from a mole or pigmented spot. Melanoma is curable surgically when discovered at early stages; however, once regional and systemic spread of the disease occurs, treatment options are limited and are generally considered ineffective [26] , [27].

The median overall survival is poor, averaging 6 to 9 months [28]. In , Huncharek et al. In , two agents, ipilimumab a fully human monoclonal antibody that blocks CTLA-4 to promote antitumor immunity and vemurafenib a potent inhibitor of mutated VE BRAF were approved in Europe and the US for the treatment of metastatic melanoma.

In addition, sorafenib an inhibitor of Raf kinase and Endostar a potent novel endogenous angiogenic inhibitor can also improve the efficacy of DTIC in patients with advanced melanoma.

More and more studies have demonstrated that DTIC combined targeted therapy can significantly improve the PFS and OS of patients with metastatic melanoma, so it is necessary to comprehensively analyze the data from clinical RCTs to evaluate the efficacy and safety of DTIC alone versus DTIC combined targeted therapy in treatment of metastatic melanoma. In addition, in terms of safety analysis, we found that DTIC combined targeted therapy had no higher incidence of most adverse events including nausea, fatigue, constipation, anemia and neutropenia but excluding vomiting compared with DTIC alone.

However, oblimersen sodium BCL-2 antisense oligonucleotide drugs in combination with DTIC had a higher incidence of adverse events including nausea, vomiting, anemia and neutropenia compared with DTIC alone. In summary, the available evidence shows that DTIC combined targeted therapy may moderately improve the overall response and the 1-year survival, although it may increase the incidence of some adverse events.

Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Background Malignant melanoma is the most aggressive and deadly form of skin cancer. Results Nine randomized controlled trials RCTs involving 2, patients were included in the meta-analysis. Conclusion These data suggested that DTIC-based combination therapies could moderately improve the overall response and the 1-year survival but increased the incidence of adverse events.

Introduction Malignant melanoma is the most aggressive form of skin cancer and is notoriously resistant to all current modalities of cancer therapy [1] , [2]. Inclusion and exclusion criteria The inclusion criteria included: i studies must be prospective randomized controlled clinical trials RCTs ; ii The subjects of the study must be diagnosed with advanced or metastatic melanoma by clinical pathology or cytology; iii they must include a single-agent DTIC or with placebo for the control group, and the comparison group s should be DTIC combined targeted therapy; iv the main outcome measures of literature must include overall response, 1-year survival and adverse events.

Literature selection and data collection process Two investigators independently selected literature on the basis of the inclusion and exclusion criteria. Download: PPT. Methodological quality assessment We evaluated the methodological quality of the included literature according to the RCT quality evaluation standard of the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.

Figure 2. Risk of bias. Definition of main outcomes Complete response was defined as disappearance of all symptoms and signs of all measurable disease, lasting for at least 4 weeks, without appearance of new lesions. Statistical methods Meta-analysis was performed using Review Manager Version 5. Results Study selection The initial search resulted in 1, potential citations, of which duplicate papers were excluded.

Study characteristics and quality assessment The eight included studies, with a total of 2, participants, were all RCTs conducted between and that were available as fully published papers.

Table 1. Summary of the characteristics of the included 8 trials. Figure 3. Figure 4. Safety Nausea was reported in five trials. Figure 5. Discussion Malignant melanoma is a malignant tumor of neural crest origin [24].